CN109516991B - Tofacitinib citrate crystal form compound and preparation method thereof - Google Patents
Tofacitinib citrate crystal form compound and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of medicines, and discloses a tofacitinib citrate crystal form compound and a preparation method thereof.A diffraction spectrum of X-ray powder obtained by measuring Cu-K α rays is shown in figure 1, and the diffraction spectrum of the X-ray powder represented by 2 theta +/-0.2-degree diffraction angles shows characteristic diffraction peaks at 3.71 degrees, 6.57 degrees, 10.88 degrees, 13.21 degrees, 15.09 degrees, 16.87 degrees, 20.01 degrees, 21.22 degrees, 25.47 degrees, 26.07 degrees, 27.69 degrees, 31.03 degrees, 32.02 degrees, 33.18 degrees and 36.74 degrees.
Description
Technical Field
The invention relates to a tofacitinib citrate crystal form compound and a preparation method thereof, belonging to the technical field of medicines.
Background
Tofacitinib citrate (Tofacitinib citrate) has a molecular structural formula shown in (I):
tofacitinib (Tofacitinib) is a novel oral JAK pathway inhibitor developed by feverfew. Unlike most other RA therapeutics currently, tofacitinib primarily targets extracellular targets, targeting intracellular signal transduction pathways, acting on the core of the cytokine network. The inhibition strength of tofacitinib (tofacitinib) on JAK3 is 5-100 times that of JAK1 and JAK 2. Tofacitinib is the pioneer drug for developing rheumatoid arthritis treatment, and the FDA approved the JAK inhibitor tofacitinib for treating adult active-life and moderate to severe Rheumatoid Arthritis (RA) patients who do not respond well to Methotrexate (MTX) on day 11, 6 of 2012.
FDA indicates that the new drug Xeljanz (tofacitinib) to feverer can be used when moderate to severe rheumatoid arthritis patients do not benefit from the conventional oral therapeutic methotrexate (methotrexate) or cannot tolerate treatment. Tofacitinib may be used alone or in combination with methotrexate and other standard therapeutic agents. The FDA approved the use of Xeljanz twice a day at a dose of 5 mg each.
The patent CN 201610817563.9 provides a new method for preparing tofacitinib citrate medicinal crystal form, citric acid is dissolved in a mixed solvent of an organic solvent and water, or the citric acid is dissolved in the water to obtain a citric acid solution; dissolving tofacitinib in a mixed solvent of an organic solvent and water, and heating to obtain a tofacitinib solution; under the heating condition, mixing a citric acid solution and a tofacitinib solution for reaction; and cooling, separating the obtained solid, and drying to obtain the crystal form. Adopts an operation method of salifying first and then recrystallizing.
The patent CN 201410740110.1 provides a preparation method of a medicinal crystal form tofacitinib citrate, which comprises the steps of taking a tofacitinib citrate raw material medicine, pumping a solvent into the solvent in a vacuum manner, heating to dissolve the tofacitinib citrate raw material medicine, and stirring for 1-2 hours under a heat preservation condition; slowly cooling to 0-50 ℃, stirring for 4-10 hours, and crystallizing; filtering and drying to obtain the medicinal crystal form tofacitinib citrate, wherein the yield reaches 90 percent, and the finished product is a stable crystal form.
Patent CN 201310046162.4 provides a preparation method of amorphous tofacitinib citrate, which is simple and convenient, and comprises the following steps: dissolving tofacitinib citrate with organic solvent at 30-50 deg.C to obtain solution, adding the solution into 15-25 deg.C water to form precipitate, standing the precipitate at 15-25 deg.C for 4-24 hr, and recovering amorphous tofacitinib citrate.
Patent CN 201310419942.9 discloses a tofacitinib hydrate and a preparation method thereof, which relates to a dihydrate crystal of 3- { (3R,4R) -4-methyl-3- [ methyl- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -3-oxo-propionitrile mono citrate and a preparation method thereof, wherein an X-ray diffraction spectrum of the dihydrate crystal comprises characteristic peaks shown by the following 2 theta angles: 6.54 °, 7.22 °, 7.94 °, 8.70 °, 10.92 °, 11.77 °, 12.32 °, 13.12 °, 14.44 °, 15.76 °, 16.57 °, 17.28 °, 18.12 °, 18.86 °.
Patent CN 201310419728.3 discloses a toltinib compound, which relates to a monohydrate crystal of 3- { (3R,4R) -4-methyl-3- [ methyl- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -3-oxo-propionitrile monocitrate and a preparation method thereof, wherein an X-ray diffraction pattern of the crystal comprises characteristic peaks expressed by the following 2 theta angles: 5.81 °, 6.92 °, 7.74 °, 8.30 °, 10.10 °, 10.51 °, 10.90 °, 11.34 °, 12.57 °, 13.65 °, 14.47 °, 15.14 °, 16.93 °.
As known to those skilled in the art, the polymorphism of a drug is an important factor affecting the quality of the drug, and has important effects on the aspects of physicochemical properties, bioavailability, related preparation quality and the like of the drug, and at present, the phenomenon is concerned by pharmaceutical workers and obviously becomes one of the indispensable contents in drug research and drug quality control. As the same medicine with different crystal forms has obvious differences in the aspects of solubility, fluidity, melting point, density, hardness, appearance, biological effectiveness and the like, the stability, bioavailability and curative effect of the medicine are influenced, the medicinal property of the tofacitinib citrate which is the next step is researched, the bioavailability is improved, and the tofacitinib citrate new crystal form has important significance for clinical application.
Disclosure of Invention
The invention provides a new crystal form of a compound shown as a formula (I), and the method has the advantages of simple operation, high yield, good reproducibility and high crystal form purity.
In order to realize the purpose of the invention, the technical scheme is as follows:
the invention provides a tofacitinib citrate crystal form compound, which is characterized in that: an X-ray powder diffraction pattern thereof expressed by 2 theta +/-0.2 DEG diffraction angles shows characteristic diffraction peaks at 3.71 DEG, 6.57 DEG, 10.88 DEG, 13.21 DEG, 15.09 DEG, 16.87 DEG, 20.01 DEG, 21.22 DEG, 25.47 DEG, 26.07 DEG, 27.69 DEG, 31.03 DEG, 32.02 DEG, 33.18 DEG and 36.74 deg.
An X-ray powder diffraction pattern of the tofacitinib citrate crystal form compound provided by the invention obtained by Cu-K α ray measurement is shown in figure 1.
The preparation method of the tofacitinib citrate crystal form compound provided by the invention comprises the following steps:
(1) pouring the solvent A into the tofacitinib citrate crude product, heating to dissolve, adding the solvent B, heating to 85 ℃, and stirring for 30-60 min;
(2) adding activated carbon for decolorization, continuously stirring for 30min, and filtering while hot;
(3) continuously stirring and dripping the obtained filtrate with precooled solvent C at 0-5 ℃, continuously reducing the dripping temperature of the solvent to crystallize, carrying out program cooling to-10-5 ℃, precipitating crystals, and carrying out heat preservation and stirring until crystallization is complete;
(4) filtering, washing and drying the crystal in vacuum to obtain the tofacitinib citrate crystal.
Preferably, in step (1), the solvent A is dimethylformamide, n-butanol, dimethyl sulfoxide or acetonitrile; the solvent B is ethyl acetate, methyl tert-butyl ether or diethyl ether; the mass volume ratio of the tofacitinib citrate crude product to the solvent A is 1: 0.5-3 g/ml.
Preferably, in the step (2), the mass of the activated carbon is 3-5% of the mass of the tofacitinib citrate crude product.
Preferably, in the step (3), the solvent C is dichloromethane, petroleum ether or n-hexane; the volume ratio of the solvent A to the solvent B to the solvent C is 1: 1-5: 1-5.5; the procedure cooling is to cool the temperature to 1-2 ℃ every 15 minutes to-10-5 ℃, the crystallization time is 5-12 h, and the stirring speed is 10-15 r/min.
Preferably, in the step (4), the vacuum drying is performed at 40-50 ℃ for 5-10 h.
Compared with the prior art, the invention has the following advantages:
(1) the tofacitinib citrate crystal form compound provided by the invention is a new crystal form different from the prior art; the preparation method is simple and easy to operate, has mild reaction conditions, and is suitable for industrial production.
(2) The invention carries out influence factor test and long-term test research on the tofacitinib citrate crystal form compound, wherein the maximum single impurity and the total impurity are not obviously increased, and all indexes are not obviously changed, thus the tofacitinib citrate crystal form compound has good stability and reproducibility, is convenient for transfer, storage and operation in the production process, and is safer for clinical medication.
(3) The tofacitinib citrate crystal form provided by the invention is used for preparing subsequent related preparations, so that the solubility of the medicine in water is well improved, and the effective bioavailability is improved.
Drawings
FIG. 1 is an X-ray powder diffraction pattern of the tofacitinib citrate crystal form compound prepared in the embodiment 1 of the invention.
FIG. 2 is a TG-DSC spectrum of the tofacitinib citrate crystal form compound prepared in the embodiment 1 of the invention.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The following embodiments are provided to explain the technical solution of the present invention in detail, and to help further understand the advantages and effects of the technical solution of the present invention, and the embodiments do not limit the scope of the present invention, which is determined by the claims.
The tofacitinib citrate crude product in the embodiment of the invention is prepared by the method in the patent CN 201610240571.1.
Example 1: preparation of tofacitinib citrate crystal form compound
(1) Adding 50g of tofacitinib citrate crude product and 25ml of dimethylformamide into a reaction bottle, heating and heating to dissolve, adding 25ml of ethyl acetate, continuously heating to 85 ℃, and stirring for 30 min;
(2) adding 1.5g of active carbon, continuously stirring for 30 minutes, and filtering while the solution is hot;
(3) stirring and dripping 25ml of 0 ℃ dichloromethane solution into the filtrate, continuously reducing the temperature to-5 ℃ along with the continuous reduction of the dripping temperature of the cold solvent after the dripping is finished, reducing the temperature to 1 ℃ every 15 minutes at the stirring speed of 10 r/min, and stirring and crystallizing for 5 hours;
(4) filtering, and vacuum drying the filter cake at 40 deg.C for 5h to obtain 49.7g white solid with yield of 99.4%, maximum single impurity of 0.01%, and purity of 99.98% (detected by HP L C).
Example 2: preparation of tofacitinib citrate crystal form compound
(1) Adding 50g of tofacitinib citrate crude product and 150ml of n-butanol into a reaction bottle, heating and heating to dissolve, adding 750ml of methyl tert-butyl ether, continuously heating to 85 ℃, and stirring for 40 min;
(2) adding 2.5g of active carbon, continuously stirring for 30 minutes, and filtering while the solution is hot;
(3) stirring and dripping 825ml of 5 ℃ petroleum ether into the filtrate, continuously reducing the temperature along with the dripping temperature of the cold solvent, continuously reducing the temperature to-10 ℃ after the dripping is finished (the temperature reduction range is 2 ℃ per 15 minutes), stirring at the speed of 15 r/min, and stirring for crystallization for 12 hours;
(4) filtration and vacuum drying of the filter cake at 50 ℃ for 10h gave 49.7g of a white solid with a yield of 99.5%, maximum single impurity of 0.01% and a purity of 99.98% (by HP L C).
Example 3: preparation of tofacitinib citrate crystal form compound
(1) Adding 50g of tofacitinib citrate crude product and 50ml of dimethyl sulfoxide into a reaction bottle, heating and heating to dissolve, adding 100ml of diethyl ether, continuously heating to 85 ℃, and stirring for 50 min;
(2) adding 2g of active carbon, continuously stirring for 30 minutes, and filtering while the solution is hot;
(3) stirring and dripping 150ml of 3 ℃ n-hexane into the filtrate, continuously reducing the dripping temperature along with the dripping temperature of the cold solvent, continuously reducing the temperature to-8 ℃ after the dripping is finished (the temperature reduction range is 2 ℃ per 15 minutes), stirring at a speed of 15 r/min, and stirring for crystallization for 10 hours;
(4) filtering, and vacuum drying the filter cake at 45 ℃ for 8h to obtain 49.7g of white solid with the yield of 99.5%, the maximum single impurity content of 0.02% and the purity of 99.99% (detected by HP L C).
Example 4: preparation of tofacitinib citrate crystal form compound
(1) Adding 50g of tofacitinib citrate crude product and 100ml of acetonitrile into a reaction bottle, heating and heating to dissolve, adding 500ml of ethyl acetate, continuously heating to 85 ℃, and stirring for 40 min;
(2) adding 2g of active carbon, continuously stirring for 30 minutes, and filtering while the solution is hot;
(3) stirring and dripping 200ml of 2 ℃ petroleum ether into the filtrate, continuously reducing the dripping temperature along with the dripping temperature of the cold solvent, continuously reducing the temperature to-5 ℃ (the temperature reduction range is 1 ℃ per 15 minutes), stirring at the speed of 10 r/min, and stirring for crystallization for 8 hours;
(4) filtering, and vacuum drying the filter cake at 50 deg.C for 10h to obtain 49.6g white solid with yield of 99.3%, maximum single impurity of 0.02%, and purity of 99.99% (HP L C detection).
Example 5: preparation of tofacitinib citrate crystal form compound
(1) Adding 50g of tofacitinib citrate crude product and 50ml of dimethylformamide into a reaction bottle, heating and heating to dissolve, adding 200ml of methyl tert-butyl ether, continuously heating to 85 ℃, and stirring for 30 min;
(2) adding 1.5g of active carbon, continuously stirring for 30 minutes, and filtering while the solution is hot;
(3) stirring and dripping 50ml of 0 ℃ dichloromethane into the filtrate, continuously reducing the dripping temperature of the cold solvent along with the continuous reduction of the dripping temperature, continuously reducing the temperature to-10 ℃ after the dripping is finished (the temperature reduction range is 1 ℃ per 15 minutes), stirring at the speed of 15 r/min, and stirring for crystallization for 5 hours;
(4) filtering, and vacuum drying the filter cake at 45 deg.C for 8h to obtain 49.7g white solid with yield of 99.4%, maximum single impurity of 0.01%, and purity of 99.98% (detected by HP L C).
Example 6: preparation of tofacitinib citrate crystal form compound
(1) Adding 50g of tofacitinib citrate crude product and 75ml of n-butanol into a reaction bottle, heating to dissolve, adding 225ml of diethyl ether, continuously heating to 85 ℃, and stirring for 45 min;
(2) adding 2.5g of active carbon, continuously stirring for 30 minutes, and filtering while the solution is hot;
(3) stirring and dripping 300ml of 0 ℃ n-hexane into the filtrate, continuously reducing the dripping temperature along with the dripping temperature of the cold solvent, continuously reducing the temperature to-8 ℃ after the dripping is finished (the temperature reduction range is 1 ℃ per 10 minutes), stirring at a speed of 15 r/min, and stirring for crystallization for 9 hours;
(4) filtering, and vacuum drying the filter cake at 50 deg.C for 7h to obtain 49.7g white solid with yield of 99.5%, maximum single impurity of 0.02%, and purity of 99.99% (HP L C detection).
Example 7: preparation of tofacitinib citrate crystal form compound
(1) Adding 50g of tofacitinib citrate crude product and 25ml of ethyl acetate into a reaction bottle, heating, adding 25ml of dimethylformamide, continuously heating to 85 ℃, and stirring for 60 min;
(2) adding 1.5g of active carbon, continuously stirring for 30 minutes, and filtering while the solution is hot;
(3) stirring and dripping 25ml of 0 ℃ dichloromethane solution into the filtrate, continuously reducing the temperature to-5 ℃ along with the continuous reduction of the dripping temperature of the cold solvent after the dripping is finished, reducing the temperature to 1 ℃ every 15 minutes at the stirring speed of 10 r/min, and stirring and crystallizing for 5 hours;
(4) filtration and vacuum drying of the filter cake at 40 ℃ for 5h gave 46.9g of a white solid with a yield of 93.8%, maximum single impurity of 0.08% and purity of 99.76% (HP L C assay).
Example 8: preparation of tofacitinib citrate crystal form compound
(1) Adding 50g of tofacitinib citrate crude product and 150ml of n-hexane into a reaction bottle, heating to raise the temperature, adding 50ml of dimethyl sulfoxide, continuously heating to 85 ℃, and stirring for 40 min;
(2) adding 2g of active carbon, continuously stirring for 30 minutes, and filtering while the solution is hot;
(3) stirring and dripping 100ml of 3 ℃ diethyl ether into the filtrate, continuously reducing the dripping temperature along with the dripping temperature of the cold solvent, continuously reducing the temperature to-8 ℃ after finishing dripping (the temperature reduction range is 2 ℃ per 15 minutes), stirring at the speed of 15 r/min, and stirring for crystallization for 10 hours;
(4) filtration and vacuum drying of the filter cake at 45 ℃ for 8h gave 47.8g of a white solid with a yield of 95.6%, maximum single impurity of 0.10% and a purity of 99.81% (HP L C assay).
Example 9: preparation of tofacitinib citrate crystal form compound
(1) Adding 50g of tofacitinib citrate crude product and 50ml of dimethylformamide into a reaction bottle, heating, adding 50ml of dichloromethane, continuously heating to 85 ℃, and stirring for 50 min;
(2) adding 1.5g of active carbon, continuously stirring for 30 minutes, and filtering while the solution is hot;
(3) stirring and dripping 200ml of 0 ℃ methyl tert-butyl ether into the filtrate, continuously reducing the dripping temperature along with the dripping temperature of the cold solvent, continuously reducing the temperature to-10 ℃ after finishing dripping (the temperature reduction range is 1 ℃ per 15 minutes), stirring at a speed of 15 r/min, and stirring for crystallization for 5 hours;
(4) filtration and vacuum drying of the filter cake at 45 ℃ for 8h gave 47.2g of a white solid in 94.4% yield, maximum single impurity 0.09% purity 98.82% (by HP L C).
Example 10: preparation of tofacitinib citrate crystal form compound
(1) Adding 50g of tofacitinib citrate crude product and 825ml of petroleum ether into a reaction bottle, heating, adding 150ml of n-butyl alcohol, continuously heating to 85 ℃, and stirring for 50 min;
(2) adding 2.5g of active carbon, continuously stirring for 30 minutes, and filtering while the solution is hot;
(3) stirring and dripping 750ml of 5 ℃ methyl tert-butyl ether into the filtrate, continuously reducing the dripping temperature along with the dripping temperature of the cold solvent, continuously reducing the temperature to-10 ℃ after finishing dripping (the temperature reduction range is 2 ℃ per 15 minutes), stirring at a speed of 15 r/min, and stirring for crystallization for 12 hours;
(4) filtration and vacuum drying of the filter cake at 50 ℃ for 10h gave 47.3g of a white solid with a yield of 94.6%, maximum single impurity of 0.11% and purity of 98.72% (by HP L C).
Example 11: preparation of tofacitinib citrate crystal form compound
Adding 50g of tofacitinib citrate crude product and 150ml of n-butanol into a reaction bottle, heating to 85 ℃, stirring for 30min, adding 2.5g of activated carbon, continuously stirring for 30min, filtering while hot, stirring the filtrate, dropwise adding 750ml of 5 ℃ petroleum ether, continuously reducing the temperature along with the dropwise adding of a cold solvent, continuously reducing the temperature to-10 ℃ after dropwise adding, reducing the temperature by 2 ℃ every 15 min, stirring at 15 r/min, stirring for crystallization for 12h, filtering, and drying a filter cake in vacuum at 50 ℃ for 8h to obtain 45.1g of white solid, wherein the yield is 90.1%, the maximum single impurity content is 0.12%, and the purity is 98.33% (detected by HP L C).
Example 12: preparation of tofacitinib citrate crystal form compound
Adding 50g of tofacitinib citrate crude product and 100ml of dimethylformamide into a reaction bottle, heating to 85 ℃, stirring for 40min, adding 2g of activated carbon, continuously stirring for 30min, filtering while hot, stirring the filtrate, dropwise adding 200ml of 0 ℃ dichloromethane, continuously reducing the dropwise adding temperature of a cold solvent, continuously reducing the temperature to-5 ℃ after dropwise adding, reducing the temperature by 2 ℃ every 15 min, stirring for 12h at a speed of 15 r/min, stirring for crystallization, filtering, and vacuum drying a filter cake at 50 ℃ for 8h to obtain 45.1g of white solid, wherein the yield is 90.9%, the maximum single impurity content is 0.12%, and the purity is 98.41% (detected by HP L C).
An X-ray powder diffraction spectrum of the tofacitinib citrate crystal form compound prepared in the example 2-12 obtained by Cu-K α ray measurement is similar to that of the example 1.
Examples 13 to 22: preparation of tofacitinib citrate crystal form compound
The method comprises the following operation steps of adding 50g of tofacitinib citrate crude product and 25ml of dimethylformamide into a reaction bottle, heating to dissolve, adding 25ml of ethyl acetate, continuing to heat to 85 ℃, stirring for 30min, adding 1.5g of activated carbon, continuing to stir for 30min, filtering while hot, stirring and dropwise adding 25ml of 0 ℃ dichloromethane solution into the filtrate, continuously reducing the dropwise adding temperature of a cold solvent, performing programmed cooling after dropwise adding, stirring for crystallization, filtering, and performing vacuum drying on a filter cake at 40 ℃ for 8h to obtain tofacitinib citrate white crystal form powder, wherein an X-ray powder diffraction spectrogram obtained by measuring the prepared crystal by using Cu-K α rays is similar to that of example 1.
Through the implementation of the examples 13 to 22, the influence of the stirring, temperature reduction and crystallization process on the crystal form can be obtained, and the experimental results are shown in the following table 1.
TABLE 1 Tofacitinib citrate preparation example results
| Examples | Temperature reduction process | Time of growing crystal/h | Stirring speed | Yield/% | Maximum single impurity/%) | Purity/%) |
| 13 | Programmed cooling to-5 deg.C, 1 deg.C every 15 min | 5 | 10 revolutions per minute | 99.3 | 0.01 | 99.99 |
| 14 | Programmed cooling to-10 deg.C, 2 deg.C every 15 min | 8 | 15 revolutions per minute | 99.2 | 0.01 | 99.99 |
| 15 | Programmed cooling to-10 deg.C, 1 deg.C every 15 min | 10 | 12 revolutions per minute | 99.4 | 0.02 | 99.98 |
| 16 | Programmed cooling to-5 deg.C, 2 deg.C every 15 min | 12 | 13 revolutions per minute | 99.0 | 0.02 | 99.99 |
| 17 | Programmed cooling to-2 deg.C, 4 deg.C every 15 min | 5 | 20 revolutions per minute | 94.1 | 0.08 | 98.13 |
| 18 | Programmed cooling to 0 deg.C, 5 deg.C every 15 min | 8 | 5 revolutions per minute | 93.4 | 0.10 | 97.94 |
| 19 | Programmed cooling to-1 deg.C, 3 deg.C every 10 min | 10 | 30 revolutions per minute | 93.7 | 0.12 | 97.26 |
| 20 | Programmed cooling to-3 deg.C, 4 deg.C every 10 min | 12 | 25 revolutions per minute | 90.1 | 0.12 | 98.11 |
| 21 | Programmed cooling to-4 deg.C and 6 deg.C every 10 min | 10 | 20 revolutions per minute | 93.7 | 0.12 | 97.26 |
| 22 | Programmed cooling to 0 deg.C, 3 deg.C every 15 min | 12 | 10 revolutions per minute | 90.1 | 0.12 | 98.11 |
The properties of the tofacitinib citrate crystal form of the invention are further illustrated by the following tests:
reference 1 is tofacitinib citrate crystal form prepared by CN 201410740110.1;
the reference 2 is tofacitinib citrate crystal form prepared by CN 201610817563.9;
Test-comparison of physicochemical Properties of novel Tofacitinib citrate Crystal form with those of the prior art
The tofacitinib citrate crystal form prepared by the invention is compared with a reference substance 1, a reference substance 2 and a reference substance 3, and the comparison condition is shown in table 2.
Table 2 comparison of the novel form of the invention with the prior art
As can be seen from Table 2, the crystal form of the invention is different from the prior art, and the XRD characteristic peak value is different; the active substance with small particle size has viscosity or poor fluidity, so that the active substance with small particle size is not suitable for direct tabletting in later preparation tests, the average particle size of the new crystal form of tofacitinib citrate is measured by a particle size analyzer to be 82-90 mu m, the crystal form is far larger than that of the crystal form in the prior art, the particle size distribution is uniform, and the angle of repose of the product is smaller than that of the crystal form in the prior art, so that the product has better fluidity, is beneficial to subsequent preparation, storage and transportation, and has great advantages in medicinal preparations; compared with the prior art, the solubility of the new crystal form is obviously increased, and the new crystal form has obvious effect on bioavailability in the future preparation research.
Test of stability of New Crystal form of tofacitinib Dicitrate
(I) stability test of influencing factors
The tofacitinib citrate crystal form prepared in examples 1-3 of the present invention, the reference 1, the reference 2 and the reference 3 were subjected to the influence factor stability test according to the 2015 chinese pharmacopoeia 9001 raw material drug and preparation stability test guideline, the thermal stability, the high humidity stability and the light stability were respectively determined by placing the tofacitinib citrate crystal form, the reference 1, the reference 2 and the reference 3 under the conditions of 60 ℃ temperature, 90 ± 5% relative humidity and 4500L x ± 500L x illumination intensity for 15 days, and the stability of the tofacitinib citrate crystal form provided by the present invention was examined, and the comparison results are shown in table 3.
TABLE 3 stability of influencing factors test results
As seen from Table 3, the crystal form of tofacitinib citrate has better stability of maximum single impurity and purity content when being placed for 15 days under the conditions of 60 ℃ of temperature, 90 +/-5% of relative humidity and 4500L x +/-500L x of illumination intensity respectively, which indicates that the crystal form is insensitive to temperature, water and illumination and is convenient for long-term storage, and the content of a reference substance has large change and poor stability.
(II) Long-term stability test
The new crystal form of tofacitinib citrate, the reference 1, the reference 2 and the reference 3 prepared in the examples 1-3 of the invention are subjected to long-term stability test according to the 2015 Chinese pharmacopoeia 9001 raw material medicament and preparation stability test guiding principle, placed for 6 months under the conditions that the temperature is 25 +/-2 ℃ and the relative humidity is 60 +/-5%, and sampled at the end of 0, 3, 6, 9, 12, 18 and 24 months to determine the properties, the maximum single impurity, the total impurity and the purity, and the results are shown in table 4.
TABLE 4 Long-term stability test results (temperature 25. + -. 2 ℃ C., relative humidity 60. + -. 5%)
As shown in Table 4, the tofacitinib citrate crystal has no obvious change in color, form and purity after being placed for 24 months at the temperature of 25 +/-2 ℃ and the relative humidity of 60 +/-5%, and has good product stability.
Claims (7)
1. A tofacitinib citrate crystal compound shown in a formula (I),
the method is characterized in that: an X-ray powder diffraction pattern thereof expressed by 2 theta +/-0.2 DEG diffraction angles shows characteristic diffraction peaks at 3.71 DEG, 6.57 DEG, 10.88 DEG, 13.21 DEG, 15.09 DEG, 16.87 DEG, 20.01 DEG, 21.22 DEG, 25.47 DEG, 26.07 DEG, 27.69 DEG, 31.03 DEG, 32.02 DEG, 33.18 DEG and 36.74 deg.
2. The tofacitinib citrate crystal form compound according to claim 1, characterized in that the X-ray powder diffraction pattern obtained by using Cu-K α ray measurement is shown in figure 1.
3. The process for the preparation of the crystal form of tofacitinib citrate according to claim 1 or 2, characterized in that it comprises the following steps:
(1) pouring a solvent A into the tofacitinib citrate crude product, heating to dissolve, adding a solvent B, heating to 85 ℃, and stirring for 30-60 min, wherein the solvent A is dimethylformamide, n-butanol, dimethyl sulfoxide or acetonitrile, and the solvent B is ethyl acetate, methyl tert-butyl ether or diethyl ether;
(2) adding activated carbon for decolorization, continuously stirring for 30min, and filtering while hot;
(3) continuously stirring and dripping pre-cooled solvent C at 0-5 ℃ into the obtained filtrate, continuously reducing the dripping temperature of the solvent to crystallize, cooling to-10-5 ℃ by a program, precipitating crystals, keeping the temperature and stirring until crystallization is complete, wherein the solvent C is dichloromethane, petroleum ether or n-hexane, and the volume ratio of the solvent A to the solvent B to the solvent C is 1: 1-5: 1-5.5;
(4) filtering, washing and drying the crystal in vacuum to obtain the tofacitinib citrate crystal.
4. The preparation method of tofacitinib citrate crystal form compound as claimed in claim 3, characterized in that: in the step (1), the mass-to-volume ratio of the tofacitinib citrate crude product to the solvent A is 1: 0.5-3 g/ml.
5. The preparation method of tofacitinib citrate crystal form compound as claimed in claim 3, characterized in that: in the step (2), the mass of the activated carbon is 3-5% of the mass of the tofacitinib citrate crude product.
6. The preparation method of tofacitinib citrate crystal form compound as claimed in claim 3, characterized in that: in the step (3), the programmed temperature reduction is carried out at 1-2 ℃ every 15 minutes, the temperature is reduced to-10-5 ℃, the crystallization time is 5-12 hours, and the stirring speed is 10-15 r/min.
7. The preparation method of tofacitinib citrate crystal form compound as claimed in claim 3, characterized in that: in the step (4), the vacuum drying refers to vacuum drying for 5-10 hours at 40-50 ℃.
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